Pressure-assisted microsyringe 3D printing of oral films based on pullulan and hydroxypropyl methylcellulose.

Oral films (OFs) continue to attract attention as drug delivery systems, particularly for pedatric and geriatric needs. However, immiscibility between different polymers limits the full potential of OFs from being explored. One example is pullulan (PUL), a novel biopolymer which often has to be blended with other polymers to reduce cost and alter its mechanical properties. In this study, the state-of-the-art in fabrication techniques, three-dimensional (3D) printing was used to produce hybrid film structures of PUL and hydroxypropyl methylcellulose (HPMC), which were loaded with caffeine as a model drug. 3D printing was used to control the spatial deposition of films. HPMC was found to increase the mean mechanical properties of PUL films, where the tensile strength, elastic modulus and elongation break increased from 8.9 to 14.5 MPa, 1.17 to 1.56 GPa and from 1.48% to 1.77%, respectively. In addition, the spatial orientation of the hybrid films was also explored to determine which orientation could maximize the mechanical properties of the hybrid films. The results revealed that 3D printing could modify the mechanical properties of PUL whilst circumventing the issues associated with immiscibility.

3D printed tablets loaded with polymeric nanocapsules: An innovative approach to produce customized drug delivery systems.

The generation of multi-functional drug delivery systems, namely solid dosage forms loaded with nano-sized carriers, remains little explored and is still a challenge for formulators. For the first time, the coupling of two important technologies, 3D printing and nanotechnology, to produce innovative solid dosage forms containing drug-loaded nanocapsules was evaluated here. Drug delivery devices were prepared by fused deposition modelling (FDM) from poly(ε-caprolactone) (PCL) and Eudragit® RL100 (ERL) filaments with or without a channelling agent (mannitol). They were soaked in deflazacort-loaded nanocapsules (particle size: 138nm) to produce 3D printed tablets (printlets) loaded with them, as observed by SEM. Drug loading was improved by the presence of the channelling agent and a linear correlation was obtained between the soaking time and the drug loading (r2=0.9739). Moreover, drug release profiles were dependent on the polymeric material of tablets and the presence of the channelling agent. In particular, tablets prepared with a partially hollow core (50% infill) had a higher drug loading (0.27% w/w) and faster drug release rate. This study represents an original approach to convert nanocapsules suspensions into solid dosage forms as well as an efficient 3D printing method to produce novel drug delivery systems, as personalised nanomedicines.

Food, physiology and drug delivery.

Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known variables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverage intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains sporadic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, the often detrimental effects of alcohol (ethanol) on dosage form performance have been widely observed experimentally, but knowledge of which has only moderately impacted on clinical practice. Here, we attempt to piece together the available subject matter relating to the influences of both solid and liquid foodstuffs on the gastrointestinal milieu and the implications for oral drug delivery, with particular emphasis on the behaviour of modified-release dosage forms, formulation robustness and drug absorption. Providing better insight into these influences, and exemplifying cases where formulations have been developed or modified to circumvent their associated problems, can help to appropriately direct the design of future in vitro digestive modelling systems as well as oral dosage forms resilient to these effects. Moreover, this will help to better our understanding of the impact of food and alcohol intake on normal gut behaviour and function.

A novel coating concept for ileo-colonic drug targeting: proof of concept in humans using scintigraphy.

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT S neutralised to pH 8.0 and a buffer salt (10% KH2PO4), which was overcoated with layer of standard EUDRAGIT S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.

The disintegration behaviour of capsules in fed subjects: a comparison of hypromellose (carrageenan) capsules and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) containing carrageenan as a gelling agent have been proposed as an alternative to conventional gelatin capsules for oral drug delivery. We have previously compared the disintegration of hypromellose(carrageenan) (Quali-V(®)) and gelatin capsules (Qualicaps) in fasted human subjects using the technique of gamma scintigraphy. This second study used the same technique with both fasted and fed human subjects. Size 0 capsules were filled with powder plugs made from lactose and did not contain croscarmellose as in the original study. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. The mean (±S.D.) disintegration time in the fasted state for the hypromellose(carrageenan) capsules was 8±2min and for gelatin 7±3min. These results were not statistically different from the data in the original study and show that the removal of the croscarmellose had no effect on the results. The mean (±S.D.) disintegration time in the fed state for the hypromellose(carrageenan) capsules was 16±5min and for the gelatin capsules was 12±4min. There was no statistical difference between the hypromellose(carrageenan) and gelatin capsules in either the fed or fasted state.

Drug solubility in luminal fluids from different regions of the small and large intestine of humans.

The purpose of this work was to study the solubility of two drugs with different physicochemical properties in luminal fluids obtained from various regions of the human gastrointestinal (GI) tract and to determine the most important luminal parameters influencing their solubility. Jejunal fluids were aspirated from healthy volunteers via an oral intubation tube. Ileal and colonic fluids were obtained from patients undergoing GI surgery. Stoma fluids were also retrieved from patients. pH and buffer capacity of all fluids were determined. Saturation solubility of prednisolone (unionisable) and mesalamine (5-aminosalicylic acid) (zwitterionic) was measured. Mean solubility of prednisolone in the different luminal fluids was 0.50 mg/mL (±0.05) and did not vary significantly between the different regions of the GI tract (ANOVA, p > 0.05). No correlation between prednisolone solubility and jejunal bile salt content was found. Mesalamine solubility increased down the GI tract: 1.97 (±0.25), 3.26 (±0.08), 6.24 (±1.13) and 7.95 (±0.21) mg/mL in jejunal, ileal, ascending and transverse/descending colonic fluids respectively. Buffer capacity also increased and in one patient was observed to range from 6.4 to 28.6 reaching 44.4 mM/L/pH unit in ileal, ascending and transverse/descending colon fluids respectively. Mesalamine solubility was found to be dependent on both buffer capacity and pH, with buffer capacity being the most important (standardized coefficient ß = 0.849, p < 0.0001) compared to pH (ß = 0.219, p < 0.05). For drugs delivered as modified release formulations it is important to consider solubility in different regions of the GI tract as significant differences can arise which will ultimately influence drug bioavailability.

The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions.

PURPOSE: Glass transition temperature (T(g)) measurements of polymers are conventionally conducted in the dry state with little attention to the environment they are designed to work in. Our aim was to develop the novel use of dynamic mechanical analysis (DMA) to measure the T(g) of enteric polymethacrylic acid methylmethacrylate (Eudragit L and S) polymer films formulated with a range of plasticizers in the dry and wet (while immersed in simulated gastric media) states. METHODS: Polymer films were fabricated with and without different plasticizers (triacetin, acetyl triethyl citrate, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, dibutyl sebacate). T(g) was measured by a dynamic oscillating force with simultaneous heating at 1 °C/min. This was conducted on films in the dry state and while immersed in 0.1M HCl to simulate the pH environment in the stomach. RESULTS: The T(g) of unplasticized Eudragit L and S films in the dry state was measured to be 150 and 120 °C, respectively. These values were drastically reduced in the wet state to 20 and 71 °C for Eudragit L and S films, respectively. The plasticized films showed similar falls in T(g) in the wet state. The fall in T(g) of Eudragit L films to below body temperature will have far-reaching implications on polymer functionality and drug release. CONCLUSIONS: Immersion DMA provides a robust method for measuring T(g) of polymer films in the wet state. This allows better prediction of polymer behaviour in vivo.

A new concept in colonic drug targeting: a combined pH-responsive and bacterially-triggered drug delivery technology.

BACKGROUND: Current approaches to colonic drug delivery exploit one of two main physiological characteristics: the pH change or increase in bacterial numbers along the gastrointestinal tract. Here, we describe a new concept in targeted delivery, which combines these triggers to improve colonic delivery. AIM: To assess the in-vivo targeting performance of a novel colonic delivery coating comprising a mixture of pH-responsive enteric polymer (Eudragit S) and biodegradable polysaccharide (resistant starch) in a single layer matrix film. METHODS: Tablets (radio-labelled) were film-coated with the dual-mechanism coating and administered in a three-way crossover study to eight healthy volunteers (i) without food, (ii) with breakfast or (iii) 30 min before breakfast. The site of intestinal disintegration was assessed using gamma scintigraphy. RESULTS: The coated tablets were able to resist breakdown in the stomach and small intestine. Consistent disintegration of the dosage form was seen at the ileocaecal junction/large intestine. The site of disintegration remained unaffected by feeding. CONCLUSIONS: The dual-mechanism (pH/bacterial) coating provides colon-specificity. Each trigger mechanism has the capacity to act as a failsafe, ensuring appropriate targeting in the gastrointestinal tract. This platform technology has potential for systemic applications or the treatment of local disorders of the large intestine, such as inflammatory bowel disease.

A scintigraphic investigation of the disintegration behaviour of capsules in fasting subjects: a comparison of hypromellose capsules containing carrageenan as a gelling agent and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) have been proposed as an alternative to conventional gelatin capsules for oral drug delivery; however, little is known about their in vivo behaviour. The aim of this study was to compare the disintegration of HPMC and gelatin capsules in fasted human subjects using the technique of gamma scintigraphy. HPMC capsules containing carrageenan as a gelling agent (QUALI-V(R), Qualicaps) and gelatin capsules (Qualicaps) of size 0 were filled with a lactose-based mixture. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. No differences in the oesophageal transit of the two types of capsules were noted, with the capsules arriving in the stomach in a matter of seconds. All the capsules disintegrated in the stomach. The mean (+/-S.D.) disintegration time for the HPMC capsules was 9+/-2min (range 6-11min). The corresponding mean time for the gelatin capsules was 7+/-4min (range 3-13min). These disintegration times were not significantly different (P=0.108, paired t-test). In conclusion, HPMC and gelatin capsules show rapid and comparable in vivo disintegration times in the fasted state. HPMC capsules containing carrageenan as a gelling agent therefore offer a practical alternative to gelatin capsules as an oral drug delivery carrier.

The formation of colonic digestible films of amylose and ethylcellulose from aqueous dispersions at temperatures below 37 degrees C.

The film forming properties of a commercial aqueous ethylcellulose dispersion (Surelease) mixed with a range of ratios of an amylose/butanol complex in the presence of a range of concentrations of a plasticiser has been studied by measuring the minimum film forming temperature (MFFT). Contrary to what was to be anticipated from the literature, it was found that an additional 4% of the plasticiser (dibutyl sebacate), normally present in the standard formulation of the ethyl cellulose dispersion, was sufficient to lower the MFFT to allow the formation of films at 35 degrees C. This was confirmed by assessment of the glass transition temperature of free films prepared by casting and drying at 35 degrees C by the application of dynamic mechanical analysis. This technique also demonstrated that the ethylycellulose and the amylose were not miscible. The ability of faecal slurry to digest the films formed at low temperatures was confirmed by the use of a batch fermenter. The extent of digestion was directly related to the amylose content of the films, ensuring the potential to provide films, which could function as colon specific coatings.

Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules.

BACKGROUND: 4-Aminosalicylic acid has the potential for use in the treatment of diseases of the colon. AIM: To assess the feasibility of delivering 4-aminosalicylic acid directly to the colon using a hydroxypropylmethylcellulose capsule coated with a mixture of amylose, a polysaccharide metabolized by bacterial enzymes in the colon, and ethylcellulose. METHODS: Seven healthy male volunteers received, on three separate occasions, an uncoated or amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsule containing 4-aminosalicylic acid Na (550 mg), or an intravenous injection of 4-aminosalicylic acid Na (135 mg). The capsules were radiolabelled with 99mTc to allow their positions in the gastrointestinal tract to be followed using a gamma camera. Plasma and urine samples were collected and assayed for 4-aminosalicylic acid and metabolite concentrations. RESULTS: The uncoated capsules broke down within 10 min in the stomach, allowing rapid and complete absorption of the drug. The coated capsules remained intact in the upper gastrointestinal tract, and had a median gastric emptying time of 61 min (interquartile range, 77 min) and a median colon arrival time of 363 min (interquartile range, 185 min). For the coated capsules, only the metabolite was detected in the plasma and/or urine after the capsules had reached the colon. CONCLUSIONS: The specific coating protected the drug until the capsule reached the colon, where 4-aminosalicylic acid was slowly released and absorbed. Thus, such a formulation has the potential for use in the treatment of inflammatory bowel disease.

The effect of polyethylene glycol 400 on gastrointestinal transit: implications for the formulation of poorly-water soluble drugs.

PURPOSE: To assess the effect of polyethylene glycol 400 (PEG 400), a pharmaceutical excipient frequently employed to enhance the solubility and bioavailability of poorly water-soluble drugs, on the gastrointestinal transit of liquid and pellet preparations in human subjects using gamma scintigraphy. METHODS: Ten, healthy male volunteers each received, on separate occasions, a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). Non-disintegrating pellets of size 1.4-1.7 mm. encapsulated within a hard gelatin capsule, were simultaneously administered on both occasions to act as a marker for solid dosage form transit. The liquid and pellet preparations were radiolabelled with 111In and 99mTc respectively thus enabling their positions within the gastrointestinal tract to be followed using a gamma camera. RESULTS: Rapid liquid emptying from the stomach was observed, with no significant difference noted in the gastric residence times of the two preparations. Caecum arrival times for the liquid preparations were significantly different by virtue of their differential rates of transit through the small intestine. The mean small intestinal liquid transit time for the control preparation was 236 min whereas the corresponding value for the PEG 400-containing test preparation was 153 min. This 35% reduction in transit time was attributed to the presence of PEG 400. Pellet transit was largely unaffected by the presence of PEG 400. CONCLUSIONS: These findings clearly demonstrate that PEG 400 has a marked accelerating effect on small intestinal liquid transit, which in turn has implications for the formulation of poorly water-soluble drugs with PEG 400.

Colonic metabolism of ranitidine: implications for its delivery and absorption.

The aim of this study was to assess the in vitro stability of ranitidine to colonic bacteria by utilising a batch culture fermentation system to simulate the conditions of the colon. Three quantities of ranitidine, 100, 200 and 500 mg, in the form of the hydrochloride salt, were introduced into individual 100 ml fermenters consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments were also run in parallel using equivalent drug quantities in buffer medium without the presence of faeces. Samples were removed at pre-determined time intervals over a 24 h period and were subsequently analysed by high-performance liquid chromatography (HPLC) for drug concentration. A selection of the samples removed from the fermenters was also analysed by conventional UV spectroscopy and mass spectrometry. Subsequent to an initial dissolution phase in the fermentation system, a marked decline in ranitidine concentration was noted over time, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted in the control buffer systems. The rate and extent of metabolism was rapid and complete within 12 and 24 h for the 100 mg and 200 mg samples, respectively, although the largest sample size, 500 mg, was only partly metabolised over the course of the experiment. UV and mass spectrometry analysis indicated that metabolism occurred via cleavage of an N-oxide bond within the molecule with the resultant loss of an oxygen atom, although further metabolic reactions are possible. Such metabolism may in part be responsible for the poor bioavailability of ranitidine from the colon.

The properties of amylose-ethylcellulose films cast from organic-based solvents as potential coatings for colonic drug delivery.

The purpose of the study was to establish the physico-mechanical and digestibility properties of water-miscible organic solvent-based amylose-ethylcellulose films as potential coatings for colonic drug delivery. Free films containing different ratios of amylose to ethylcellulose were cast from the water-miscible organic solvent, ethyl lactate, in combination with the plasticiser, dibutyl sebacate. The resultant mixed films were characterised in terms of tensile strength and elasticity, polymer miscibility, permeability, and digestibility under simulated colonic conditions. Films containing higher concentrations of amylose displayed increasing weakness and softness and faster permeation to hydrogen ions compared to films with lower amylose content. No apparent miscibility was detected between the amylose and ethylcellulose, regardless of film composition. The films were found to be susceptible to digestion by bacterial enzymes within a simulated colonic environment. The extent of digestion was directly proportional to the amount of amylose present within the film. Overall, the results suggest that such amylose-ethylcellulose films could be used as coatings for drug delivery to the colon.

The potential of organic-based amylose-ethylcellulose film coatings as oral colon-specific drug delivery systems.

Amylose-ethylcellulose film coatings obtained from organic-based solvents were investigated as potential vehicles for colonic drug delivery. Amylose, in the form of an amylose-butan-1-ol dispersion, and ethylcellulose, dissolved in either ethyl lactate, ethanol, or propanol and plasticized with dibutyl sebacate, were mixed in various proportions and applied using a fluidized bed coater to achieve a range of film thicknesses on 5-aminosalicylic acid pellets. Drug release from the coated pellets was assessed under gastric and small intestinal conditions in the presence and absence of pepsin and pancreatin using dissolution methodology, and also within a simulated colonic environment involving fermentation testing with human feces in the form of a slurry. Under upper gastrointestinal tract conditions, the rate and extent of drug release were found to be related to the thickness of the coating and the ratio of amylose to ethylcellulose within the film. Modeling of the drug release data revealed that the ratio was more important than coat thickness in controlling drug release, irrespective of the solvent used for coating. Coatings with a thick film and/or low amylose content were relatively impermeable and able to delay drug release under conditions mimicking the upper gastrointestinal tract. Furthermore, drug release was unaffected by the presence of pepsin and pancreatin and by long-term storage. Under simulated colonic conditions, drug release was more pronounced from coating formulations containing higher proportions of amylose. Colon-specificity can therefore be achieved using such systems by judicious choice of the appropriate ratio of amylose to ethylcellulose and coat thickness.

Formulation of ranitidine pellets by extrusion-spheronization with little or no microcrystalline cellulose.

The present study was concerned with the feasibility of formulating ranitidine into pellets with a range of alternative excipients in place of microcrystalline cellulose (MCC). Eight ranitidine formulations employing two or more of the excipients lactose, barium sulfate, glyceryl monostearate, and MCC were processed by extrusion-spheronization, and characterized according to a series of physico-mechanical and dissolution criteria. Formulations containing lactose produced unsatisfactory pellets of wide size distribution and irregular shape, whereas formulations incorporating barium sulfate and glyceryl monostearate with or without MCC resulted in relatively spherical pellets of narrow size distribution and good mechanical properties. Ranitidine release was found to be rapid and virtually complete within 15 min, regardless of the pellet formulation. A direct relationship was observed between the concentration of MCC in the formulation and the properties of the pellets. In general, the higher the concentration of MCC, the rounder, stronger, and less friable the pellets. However, even pellets without MCC were also successfully prepared with a superior size distribution and shape over those with MCC. Overall, these results confirm that ranitidine can be formulated into pellet dosage forms with little or no MCC by the extrusion-spheronization process.